CN1040423C - Enzymatic resolution of endo bicyclo {2,2,1} heptan-2-01 and derived pharmaceutical agents - Google Patents

Enzymatic resolution of endo bicyclo {2,2,1} heptan-2-01 and derived pharmaceutical agents Download PDF

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CN1040423C
CN1040423C CN90109076A CN90109076A CN1040423C CN 1040423 C CN1040423 C CN 1040423C CN 90109076 A CN90109076 A CN 90109076A CN 90109076 A CN90109076 A CN 90109076A CN 1040423 C CN1040423 C CN 1040423C
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heptan
dicyclo
interior
alcohol
norborneol
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尼古拉斯·A·萨科曼诺
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Abstract

Process for the pancreatic lipase mediated transesterification method for the optical resolution of endo-norborneol; derived optically active 5-(3-(exo-bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl)-3,4,5,6-tetrahy dropyrimid in-2(1H)-ones; and stepwise process and intermediates therefor.

Description

In split and institute's deutero-medicament to the enzymatic of dicyclo [2.2.1] heptan-2-alcohol
The present invention relates to a kind of preparation (+)-(2R)-interior to norborneol and (-)-(2S)-interior to norborneol and make them further change into the method for following two medicines respectively, these two medicines are respectively formula (I) 5-(3-((2S)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyls)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone and formula (II) enantiomorph 5-thereof (3-((2R)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone.
Figure C9010907600041
The invention still further relates to these two kinds has optically active concrete medicine itself, and the synthetic used intermediate (formula of back (III)-(VI)) of these medicines.
(2R)-interior to norborneol also can be described as (2R)-interior to dicyclo (2.2.1) heptan-2-alcohol or (1S, 2R, 4R)-dicyclo (2.2.1) heptan-2-alcohol.Equally, its enantiomorph (2S)-interior to norborneol also can be described as (2S)-interior to dicyclo (2.2.1) heptan-2-alcohol or (1R, 2S, 4S)-dicyclo (2.2.1) heptan-2-alcohol.Similarly, in (2S) that is derived-export-oriented dicyclo (2.2.1) heptan-2-base and (2R)-export-oriented dicyclo (2.2.1) heptan-2-base substituting group, also can be called (1S, 2S, 4R)-dicyclo (2.2.1) heptan-2-base and (1R, 2R, 4S)-dicyclo (2.2.1) heptan-2-base.
People such as Saccomano briefly disclose some and can be used as the compound of thymoleptic in disclosed International Patent Application WO 87/06576, formula of the present invention (I) and (II) compound be exactly wherein valuable especially person.Though above-mentioned reference specifically discloses racemic 5-(3-((2S)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone, but do not have specifically to disclose the optically active body that itself exists, do not disclose their any concrete preparation method yet.Formula of the present invention (I) and (II) compound is also valuable especially to asthma and some treating for skin disease.
Up to now, have optically active (2R) and (2S)-interiorly all obtain: with the export-oriented norborneol phthalic acid monoesters that optically active phenylethylamine compounds resolution of racemic is arranged in order to method down to the norborneol compounds, be hydrolyzed into optically active export-oriented norborneol class, used CrO 3Be oxidized to optically active norbornane ketone, used Li (S-Bu) at last 3BH is reduced into desired interior to isomer (Irwin etc., J.Am.Chem.Soc., 98:8476-8481,1979).According to this piece reference, in going out with the incomplete reduction enrichment of horse liver alcohol dehydrogenase catalysis racemize 2-norbornane ketone to norborneol class enantiomorph, with the incomplete oxidation of the export-oriented norborneol of this enzyme catalysis racemize then enrichment go out to norborneol class isomer.(-)-export-oriented norborneol also makes (Brown etc., J.Org.Chem., 47:5065-5069,1982) by the asymmetric hydroboration of norbornylene.
Up to now, once utilized and almost carrying out splitting some chirality alcohols (Kirchner etc., J.Am.Chem.Soc.107:7072-7076,1985) in the anhydrous organic solvent by the catalytic transesterification of porcine pancreatic lipase.For example, racemic sec-n-octyl alcohol and butyric acid 2,2,2-trichloro ethyl ester generate (R)-butyric acid 2-monooctyl ester of high-optical-purity with 47% transformation efficiency.But this method is when being applied to racemic export-oriented norborneol, the pure and mild product butyric ester that is recovered to all still is racemic basically, also is so (this can when not having enzyme underaction prove) even mediate this transesterification with enzyme clearly.
Although the transesterification with the export-oriented norborneol of lipase catalysis can not provide the feasible method that export-oriented isomer is carried out optical resolution, we find that still this method to the optical resolution to norborneol in above-mentioned is-kind of simple but effective method.Therefore, one aspect of the present invention relate to preparation have optically active in to the method for dicyclo (2.2.1) heptan-2-alcohols (interior) to norborneol, this method comprises the steps:
(a) in the presence of a kind of Mammals steapsin, in substantially anhydrous reactionlessness organic solvent, in racemic,, carry out part ester group permutoid reaction between the 2-trichloro ethyl ester to the pure and mild butyric acid 2,2 of dicyclo (2.2.1) heptan-2-;
(b) from the mixture of gained, isolate unreacted (-)-(2S) with following formula-interior to dicyclo (2.2.1) heptan-2-pure and mild (2R)-interior to dicyclo (2.2.1) heptan-2-alcohol butyric ester, This ester hydrolysis is generated enantiomorph (+)-(2R) with following formula-interior to dicyclo (2.2.1) heptan-2-alcohol ((2R)-interior to norborneol).
Figure C9010907600062
More than and the used phrase " reaction-inert solvent " in this paper other places refer to a kind of like this solvent, it can not have the mode of disadvantageous effect and raw material, reagent, intermediate or product generation interaction with certain productive rate to wanted product.
In the preferred embodiment of this method, the source of enzyme is a pig, solvent is an ether, resulting have optically active (2R)-and (2S)-interior to dicyclo (2.2.1) heptan-2-alcohol in the presence of triphenyl phosphine and azepine diethyl dicarboxylate further with 3-hydroxyl-4-p-methoxybenzaldehyde, generate respectively optically active formula (III) aldehyde 3-arranged ((2S)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-3-of 4-methoxybenzaldehyde and formula (IV) ((2R)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-the 4-methoxybenzaldehyde. Then these two compounds further transform an accepted way of doing sth (I) and (II) compound through following step and intermediate:
(a) in about 25-100 ℃ temperature range, in the presence of the piperidines of catalytic amount, make optically active 3-(export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-methoxybenzaldehyde (III) or (IV) and the 2-cyanoacetic acid of at least 2 molar equivalents in pyridine, react, generation has following formula V or optical activity 3-(VI) (3-(export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) trimethylene cyanide, and wherein Y is CN;
(b) make described trimethylene cyanide hydration with ordinary method, generate and to have following formula V or optical activity 3-(VI) (3-(export-oriented dicyclo (2.2.1) heptan-the basic chlorine of 2-)-4-p-methoxy-phenyl) glutaramide, wherein Y is CONH 2
(c) effect by excessive one mole lead tetraacetate makes the cyclisation in pyridine of described glutaramide, generation has following formula (I) or optical activity 5-(II) (3-(export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone.
The invention still further relates to and belong to following formula (I) and some optically active compounds that always can't obtain (II), also relate to the optical activity intermediate of formula V and formula (VI),
Figure C9010907600081
Figure C9010907600091
Wherein Y be-CN or-CONH 2
All respects of the present invention are all easy to implement.In view of the above, interior to norborneol and butyric acid 2,2 the racemize that is molar equivalent substantially, the 2-trichloro ethyl ester is dissolved in the reactionlessness organic solvent.Preferred in this case solvent is an ethers, and for example substantially anhydrous while is dissolved ether, diisopropyl ether, the tetrahydrofuran (THF) Huo diox of specifying reactant again easily.Mammals steapsin (the preferred porcine pancreatic lipase that easily obtains from commercial source) divides some parts of addings with dry powder, and add-on is for keeping the required amount of rational transesterify speed.Temperature is very crucial, usually about 15-40 ℃ scope.If temperature is low excessively, speed of response can be slow excessively; The too high rapid inactivation of enzyme that then can make of temperature of reaction.Following the tracks of reaction with analysis means (is conveniently to utilize and differentiates raw material and ester products easily 1H-NMR), and reach about 40-50% termination reaction when complete in reaction, so as to improve as far as possible with (2S) that reclaim-interior to norborneol and (2R)-butyric acid in to the optical purity of norborneol ester.These products separate with ordinary method, are to use chromatography easily., generate (2R)-interior the ester hydrolysis with ordinary method well known in the art to norborneol.
According to the present invention, the disclosed method of WO87/06576 of quoting and being summarized according to the front, resulting optical activity (2R) and (2S)-interiorly change into following formula (III) and aldehyde (IV) respectively to norborneol.
In addition, according to the present invention, make the cyanoacetic acid condensation of following formula (III) or aldehyde (IV) and at least two molar equivalents, generate formula V or dintrile (VI), wherein Y is CN.Be conveniently, exist down, in pyridine, carry out above-mentioned condensation reaction at general excessive one mole secondary amine (preferably do not have secondary sterically hindered amines, cough up alkane) as piperidines or piperazine.Pyridine also partly plays the effect of basic catalyst.Though it is the first few stage of this reaction can at room temperature carry out, the most complete in the temperature reacting by heating (comprising decarboxylic reaction) of about 80-110 ℃ scope.
Use ordinary method that formula V or dintrile hydration (VI) are become formula V or diamide (VI) then, wherein Y is CONH 2Way is easily, under the temperature of about 0-30 ℃ scope, at excessive N a 2CO 3Exist down, make the H of dintrile and half molar weight 2O 2In the reactionlessness water-containing organic solvent, react.
Make the diamide cyclisation of formula (VI) form formula (I) or optical activity 5-(II) (3-(export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone at last.Preferably utilize excessive one mole lead tetraacetate to carry out this reaction as solvent with excess pyridine.Temperature is not crucial, and the temperature of 0-60 ℃ of scope is generally just satisfactory.Be to adopt room temperature easily, can avoid heating or refrigerative expense like this.
Go up pointed for the 25th page as the patent application WO87/06576 that quotes previously, 5-(3-(export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone has the vitro inhibition activity to the phosphodiesterase that is made by rat cerebral cortex.With this compound the application aspect the curing asthma more relevant be it to the inhibition activity of the phosphodiesterase that derives from Guinea pig lung, this will be among the embodiment 1 below describes in detail, in embodiment 1 formula of the present invention (I) and (II) optically active compound show same activity.The application of The compounds of this invention aspect curing asthma also is reflected in, and they can suppress the migration of eosinocyte to the sensitization lung tissue in infecting antigenic cavy body, and this will describe in detail in embodiment 2.The compounds of this invention is reflected in the intravital hydroderma of cavy that they can suppress to use ovalbumin sensitization by psoriasis due to the contact allergy and the application in the dermatitis, and this will describe in detail in embodiment 3.
When with formula (I) or (II) compound or corresponding racemic compound carry out whole body therapeutic to asthma or inflammatory tetter, no matter take with what approach, its dosage-as all be about 0.01-2 mg/kg/day (typical human body that counterweight is 50 kilograms is the 0.5-100 mg/day), take with single dose or fractionated dose.Certainly, according to the specific nature of concrete compound and various diseases, the attending doctor can advise the dosage outside this scope voluntarily.Treatment is during asthma, and is general preferred (dripping or spray) in the suction port in the aerosol intranasal, and conventional oral.But if the patient can not swallow, perhaps the buccal absorption ability is because other is former thereby impaired, and then preferred general route of administration is parenteral route (intramuscular, an intravenously).During treatment inflammatory tetter, preferred route of administration is oral or topical administration.During treatment inflammatory airway disorders, preferred route of administration is to take in the nose or oral.
Compound of the present invention is generally taken with the form of pharmaceutical composition, comprises one of described compound and a kind of pharmaceutical carrier or thinner in the composition.This based composition generally is to utilize to be suitable for required solid or liquid vehicle or the thinner of taking mode, and prepare in a usual manner: oral dosage form is tablet, soft or hard capsule, suspension agent, granula, pulvis etc.; It is injection solution or injectable suspensions etc. that parenteral is taken formulation; Exterior-applied formulation is solution, washing lotion, ointment, ointment etc., and these formulations generally contain about 0.1-1% (W/V) activeconstituents; In the nose or suck and be generally 0.1-1% (W/V) solution when taking.
The present invention illustrates with the following example, but is not limited to details wherein.
Embodiment 1
The inhibition of lung phosphodiesterase (PDEIV)
With guinea pig lung tissue with the concentration of 10 milliliters in every gram tissue place homogenate buffer (20mM Bistris.5mM 2 mercapto ethanol, 2mM benzamidine, 2mMEDTA, 50mM sodium acetate, pH6.5).With TekmarTissumizer at full speed with tissue homogenate 10 seconds.In damping fluid, add phenylmethylsulfonyl fluoride (PMSF, the aqueous isopropanol of 50mM), homogenate immediately then, the final concentration that makes PMSF is 50 μ M.Homogenate was descended centrifugal 10 minutes in 4 ℃ with 12,000 * g.Supernatant liquor filters with gauze and glass fiber, then in being added under 4 ℃ on 17 * 1.5cm DEAE-Sepharose CL-6B post of using the homogenate buffer pre-equilibration.The flow velocity that is adopted is 1 ml/min.After supernatant liquor is crossed post, wash post with the homogenate buffer that doubles the supernatant liquor volume at least.Linear gradient elution with the 0.05-0.1M sodium acetate goes out phosphodiesterase.Collect 100 5 milliliters fraction.According to by ( 3H) the relevant fraction of the active reservation of the special PDEIV of the ability of cAMP hydrolysis and known PDEIV mensuration.
The preparation of test-compound: with each compound with 10 -2The concentration of M is dissolved in DMSO, and water was with dilution (4 * 10 in 1: 25 then -4The M compound, 4%DMSO).4%DMSO is carried out further serial dilution reach desired various concentration.The final concentration of DMSO is 1% in the testing tube.
Do three parts of parallel tests, under 0 ℃, following reagent be added to successively (all concentration that provide are the final concentration in the testing tube) in 12 * 75 millimeters Glass tubings:
25 μ l compounds or DMSO (1%, be used for contrast or blank) 25 μ l assay buffer (50mM Tris, 10mM MgCl 2, pH7.5)
25μl〔 3H〕-cAMp(1μM)
25 μ l PDEIV enzymes (doing when blank) enzyme pre-incubation 10 minutes in boiling water bath.
Reaction tubes was placed 10 minutes in water-bath (37 ℃) after vibrating, and when the time comes each pipe was placed reaction is stopped in boiling water bath.Each pipe is placed ice bath and adds (0.5 milliliter of lavation buffer solution at every pipe, 0.1M HEPES/0.1M NaCl, pH8.5). the content in every pipe is added in advance on the Affi-Gel601 post of crossing with the lavation buffer solution balance (boride affinity gel, bed volume are 1.2 milliliters).With 2 * 6 milliliters of lavation buffer solutions wash out ( 3H) cAMP, then with 6 milliliters of 0.25M acetate wash-outs go out ( 3H) 5 ' AMP.After shaking, get 1 milliliter of elutriant and be added in 3 milliliters of Atomlight scintillation solutions that are contained in the suitable scintillation vial, shake the back to ( 3H) counting.
Suppressing per-cent is determined by following formula:
Figure C9010907600131
IC 50Be defined as will ( 3H) cAMP is special is hydrolyzed into ( 3H) reaction of 5 ' AMP suppresses 50% compound concentration.
In this test, racemize 5-(3-(export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 IC that (1H)-ketone showed 50Be 0.5 μ M.In this test, basic identical to two viewed level of activity of corresponding optical activity enantiomeric compounds.
Embodiment 2
Eosinocyte is to infection in the cavy body
The inhibition of antigenic sensitization lung tissue migration
The normal Hartley cavy (300-350 gram) that Charles River Laboratories is sold stable breeding 5-7 days.Antiovalbumin IgG1 or salt solution in contrast with 0.5 mg/kg makes cavy sensitization then.After 48-72 hour, be one group with six animals and give every oral the most nearly compound of 32 mg/kg of cavy, make carrier with 2% tween 80.1-1.5 after hour, receive bright for the pyrrole of animal abdominal injection 5 mg/kg.After taking pyrrole and receiving bright 30 minutes, make animal be exposed in the 0.1% ovalbumin aerosol 10 minutes, infect at Tri-R Airborne that the aerosol through 15 minutes dissipates the phase in the instrument then (pressurized air flow velocity=20 liter/minute, primary air flow velocity=8.4 liter/minute).From this instrument, take out cavy and be placed in the cage 18 hours, put to death then and carry out lung lavage subsequently.
Kill cavy with 3 milliliters of urethanes (0.5 grams per milliliter), tracheae is separated from surrounding tissue.Around the loose surgical thread of fastening of tracheae, and on tracheae, do an otch apart from the about 1-2 centimeters of thymus gland.In tracheae, insert No. 15 blunt nosed liquid feeding syringe needles of 1 cm long, and linear system tightly with fixed needle.With the lavation five times in lung of 3 * 10 mL of saline.Reclaim about 20-25 milliliter, and place 50 milliliters of tapered tubes that are placed on ice.Telling 0.475 milliliter of irrigating solution is added in the polystyrene tube that 0.025 milliliter of 2%Triton X-100 stain remover is housed and (does parallel two parts).
The sample of telling that contains Triton is diluted with 1 milliliter of PBS/0.1%Triton damping fluid (pH7.0).From the sample after the dilution, tell 0.025 milliliter, add 0.125 milliliter of PBS/0.1%Triton damping fluid again.Add solution and the 1 microlitre/milliliter hydrogen peroxide of 0.300 milliliter of 0.9 mg/ml o-phenylenediamine dihydrochloride (OPD) in 50mM Tris damping fluid/0.1%Triton (pH8.0), thereby begin to carry out colorimetric reaction.Be incubated after 5 minutes, add 0.250 milliliter of 4M sulfuric acid stopped reaction.Measure the optical density(OD) of mixture at the 490nm place, and subtracting background optical density(OD) (blank pipe).
Two parallel optical density readings are obtained on an average the single numerical value of every animal.With 6 numerical evaluation average optical that obtain in every treated animal+/-standard deviation.Calculated owing to antigen infects the special EPO reaction produces by following formula: 1000 * (average optical (infecting and sensitization)-average optical (infect and not sensitization)) are calculated owing to the medicine pre-treatment suppresses the per-cent that special EPO reacts by following formula:
In this test, racemize 5-(3-(export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-methoxyl group-3,4,5, the ED that 6-tetrahydropyrimidine-2 (1H)-ketone shows 50Be 10 mg/kg.
Embodiment 3
The guinea pig skin oedema that suppresses ovalbumin sensitization
Get four cavys (Hartley, male, 350-400 restrains) and use antiovalbumin IgG1 antibody sensitized.Give the test-compound of two oral 32 mg/kg of cavy, two cavys are taken carrier (2% tween-80) in addition.After taking medicine 1 hour, give 1 milliliter of Evan Blue of every cavy intravenous injection (7 mg/ml), use 0.1 milliliter of ovalbumin (0.1%) or PBS that its skin is carried out intracutaneous then and infect.Infect after 20 minutes, take off skin and the hydroderma position that detects by an unaided eye (the circular Bluepoint of infection site).
Ovalbumin infects the position that causes infecting ovalbumin on the skin and forms oedema, and the PBS infection produces hydroderma hardly.Taken racemize 5-(the export-oriented dicyclo of 3-(2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl for two)-3,4,5, the cavy of 6-tetrahydropyrimidine-2 (1H)-ketone, compare with the oedema of taking the carrier animal, the intensity and the area of antigen infection site Bluepoint all obviously reduce.
This result shows that this compound is to effective by the guinea pig skin oedema of antigen induction.
Embodiment 4
(+)-(2R)-and (-)-(2S)-
In to norborneol ((2R)-and (2S)-
In to dicyclo (2.2.1) heptan-2-alcohol)
To be dissolved in 40 milliliters of ether to norborneol (5.0 grams, 44.6 mmoles) and butyric acid trichloro ethyl ester (5.1 grams, 23.2 mmoles) in the racemize.Add 4A molecular sieve (4 gram) and at room temperature stir this mixture.In the time of 0.20,43,50 and 67 hour, add 0.5 gram, 1.0 grams, 1.0 grams, 1.0 grams and 0.5 gram porcine pancreatic lipase (Sigma, II type, crude product) respectively.By 1The HNMR monitoring reaction, about 50% fully the time (92 hours) use diatomite filtration and vacuum-evaporation under situation about not heating.(alcohol easily distils).Thick resistates dodges the formula chromatography with the gradient elution system of 2-25% ether/hexane on silica gel, obtain 2.9 grams (15.9 mmole) (2R)-butyric acid in to the transparent oily matter of norborneol ester and 1.8 restrain (16.0 mmole) (2S)-interior to the norborneol white solid.(α) D=-2.03 °; E.e.87.2% (by (S)-α-methoxyl group-α that derives-(trifluoromethyl) toluylic acid (MTPA) ester 1HNMR records).Because specific rotation is too little, so more reliable as measuring of optical purity by the e.e. value of NMR mensuration.
With in the butyric acid that is reclaimed to norborneol ester (2.3 gram, 12.6 mmoles), K 2CO 3(2.5 grams, 18.0 mmoles) and methyl alcohol (65 milliliters) stirred 64 hours under room temperature, distributed between ether and water then.Organic moiety water and salt water washing, dry (Na 2SO 4), filter and vacuum concentration, obtain 1.3 grams (11.6 mmoles, productive rate 91.9%) (2R)-interior to norborneol.(α) D=+2.7 °; E.e.87.6% (according to the MTPA ester 1HNMR).
Repeat these steps, but that transesterify only proceeds to is 44% complete, resulting (2S)-interior lower to the norborneol optical purity, and productive rate is higher than 90%, (α) D=-0.88, e.e.71.4% is (according to above-mentioned 1HNMR); Resulting (2R)-interior higher to the norborneol optical purity, productive rate is 56.4%, e.e. greater than 95% (according to above-mentioned 1HNMR).
Embodiment 5
3-((2S)-export-oriented dicyclo (2.2.1) heptan
-2-base oxygen)-the 4-methoxybenzaldehyde
Azepine diethyl dicarboxylate (28.5 grams, 27.7 milliliters, 0.141 mole) and triphenyl phosphine (36.9 grams, 0.141 mole) are dissolved in 200 milliliters of tetrahydrofuran (THF)s.In this solution, add (+)-(2R)-interior, add 3-hydroxyl-4-methoxybenzaldehyde (isovanillin then to the solution of norborneol (7.9 grams, 0.0705 mole) in 100 milliliters of tetrahydrofuran (THF)s; 21.4 gram, 0.141 mole) solution in 100 milliliters of tetrahydrofuran (THF)s.The gained mixture heating up refluxed two days, and cooling then with 1.5 liters of ether dilutions, is used water (2 times), 0.5NNaOH (2 times), water and the salt water washing of half volume, dry (Na successively 2SO 4), after the elution, resistates carries out chromatography on silica gel, carry out gradient elution with the 0-10% ethyl acetate, obtains 8.5 gram these title product (49%), (α) D=+24.5 ° (deuterochloroform).
Using the same method is converted into 3-((2R)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-methoxybenzaldehyde to (-)-(2S)-interior to norborneol, and it is identical with title compound that the physical properties of this compound is removed the optically-active outer symbol.
Embodiment 6
3-(3-((2S)-export-oriented dicyclo
(2.2.1) heptan-2-base oxygen)
P-methoxy-phenyl) trimethylene cyanide
The title product (8.5 grams, 0.0346 mole) of last example is dissolved in 250 milliliters of pyridines.Add cyanoacetic acid (14.6 grams, 0.171 mole) and piperidines (5 milliliters), this mixture was stirred under room temperature 4 hours, stirred 2 hours down in 60 ℃ then, stirred 24 hours down in 100 ℃ at last.Coupling vacuum stripping is removed and is desolvated, and residue is dissolved in 250 milliliters of ethyl acetate, uses saturated NaHCO 3, then wash with water, again behind the stripping with Virahol/isopropyl ether crystallization, obtain 5.84 gram (54%) these title compounds, m.p.121-123 ℃, (α) D=+17.8 ° (deuterochloroform).
The enantiomorph product with last example of using the same method is converted into 3-(3-((2R)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) trimethylene cyanide, it is identical with this title product that the physical properties of this compound is removed the optically-active outer symbol.
Embodiment 7
3-(3-((2S)-export-oriented dicyclo
(2.2.1) heptan-2-base oxygen)
-4-p-methoxy-phenyl) glutaramide
To 150 milliliters of 2: 1 acetone: H 2Add 5 milliliters of 10%Na in the last embodiment title product among the O (volume) (5.82 grams, 0.0188 mole) 2CO 3, drip 3O%H then 2O 2(8 milliliters, 0.094 mole), keeping temperature simultaneously is O-5 ℃.Stir under the room temperature after 16 hours, in this mixture impouring water (300 milliliters) and ethyl acetate (5O0 milliliter), stir the mixture 1 hour with dissolving all solids thing.Tell organic layer, use H 2O and salt water washing, dry and stripping gets the crystalloid resistates, it is dodged the formula chromatography on silica gel, with 15: 1CH 2Cl 2: CH 3OH makes eluent, obtains 3.7 these title product of gram, m.p.l98.5-199.5 ℃; Infrared (KBr) cm -13335,3177,2952,1674,1631,1516,1406,1256,1142,1003,809,685,641cm -1
The enantiomorph product with last embodiment of using the same method changes into 3-(3-((2R)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) glutaramide, it is identical with this title product that the physical properties of this compound is removed the optically-active outer symbol.
Embodiment 8
The title product (3.7 grams, 0.0107 mole) of last embodiment is dissolved in 250 milliliters of pyridines, to wherein adding 250 milliliters of lead tetraacetates (10.92 grams, 0.0246 mole) in the pyridine.Stir after 30 hours, with the reactant coupling vacuum stripping, with 100 milliliters of CH 2Cl 2Dissolving oily resistates is used H 2O and salt water washing, dry (Na 2SO 4), stripping, the gained solids is developed with ether, obtains this title product of white solid, 1.21 grams, m.p.202-203 ℃, (α) D=+14.45 ℃ (deuterochloroform).
With the enantiomorph product of last embodiment being changed into 5-(3-(2R)-export-oriented dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl with quadrat method)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone, it is identical with this title compound that its physical properties is removed the optically-active outer symbol.

Claims (3)

  1. One kind prepare optically active (2S) arranged-interior to dicyclo (2.2.1) heptan-2-alcohol or (2R)-interior method to dicyclo (2.2.1) heptan-2-alcohol, this method comprises the steps:
    (a) in the presence of the Mammals steapsin, in substantially anhydrous reactionlessness organic solvent, carry out in the racemize to the pure and mild butyric acid 2 of dicyclo (2.2.1) heptan-2-, 2, part transesterification reaction between the 2-trichloro ethyl ester, generation contains described (2S)-and interior to dicyclo (2.2.1) heptan-2-pure and mild (2R)-interior mixture to dicyclo (2.2.1) heptan-2-alcohol butyric ester, described enzyme, the ratio of itself and matrix is 1 to 100 molar percentage;
    (b) from described mixture, isolate described (2S)-interior to dicyclo (2.2.1) heptan-2-alcohol; Or
    From described mixture, isolate described (2R)-interior, and its hydrolysis is generated described (2R)-interior to dicyclo (2.2.1) heptan-2-alcohol with ordinary method to dicyclo (2.2.1) heptan-2-alcohol butyric ester.
  2. 2. the process of claim 1 wherein that lipase is from pig.
  3. 3. claim 1 or 2 method, wherein reaction-inert solvent is an ether.
CN90109076A 1989-11-13 1990-11-12 Enzymatic resolution of endo bicyclo {2,2,1} heptan-2-01 and derived pharmaceutical agents Expired - Fee Related CN1040423C (en)

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